US20070031493A1 - Pharmaceutical compositions - Google Patents

Pharmaceutical compositions Download PDF

Info

Publication number
US20070031493A1
US20070031493A1 US11/545,650 US54565006A US2007031493A1 US 20070031493 A1 US20070031493 A1 US 20070031493A1 US 54565006 A US54565006 A US 54565006A US 2007031493 A1 US2007031493 A1 US 2007031493A1
Authority
US
United States
Prior art keywords
pharmaceutical composition
fluvastatin
release
composition according
matrix material
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/545,650
Inventor
Jan-Erik Lofroth
Jones Odman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=20404165&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20070031493(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Priority to US11/545,650 priority Critical patent/US20070031493A1/en
Publication of US20070031493A1 publication Critical patent/US20070031493A1/en
Priority to US12/795,801 priority patent/US20100291217A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2009Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • A61K9/2018Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to pharmaceutical compositions for sustained release comprising a water soluble salt of the HMG-CoA reductase inhibitor fluvastatin as active ingredient, said composition being selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.
  • a sustained-release tablet releases the drug during several hours, typically more than 3 hours and less than 30 hours.
  • Other commonly used terms such as “controlled release”, “extended release”, “prolonged release”, etc., all comply with the definition of a product that releases the drug typically over more than 3 hours.
  • sustained release of a drug.
  • the different formulations all aim to have release of the drug from the formulation, rather than the absorption process of the drug, as the rate limiting step.
  • approaches based on the control of, e.g., dissolution, diffusion, swelling, osmotic pressure, complexation, ion-exchange, etc., can be employed.
  • the actual approach taken for a given drug depends inter alia on the physical chemical properties of the drug.
  • One of these is the solubility of the drug, which has a major impact on the pharmaceutical formulation strategy.
  • a high solubility of the drug substance may induce problems, as discussed further below.
  • sustained release can be obtained according to the following principles, or combinations of them:
  • the gastrointestinal fluids penetrates the membrane, the drug is dissolved and thereafter diffuses out of the coated particle through the membrane.
  • the driving force for diffusion is the concentration of the drug in the aqueous solution created by the penetrating gastrointestinal fluid.
  • the solubility the higher the aqueous concentration of the drug in the matrix, and the faster the diffusional transport of the drug over the membrane.
  • the transport rate with this type of formulation is dictated by the pores in the membrane. Nevertheless, it is the solubility which creates a high concentration gradient over the membrane and which then is important for the transport rate from the formulation.
  • the drug release from sustained release formulations is related to the drug solubility.
  • the higher the water solubility of the drug the faster the drug release and the shorter the duration of drug delivery.
  • a fast release of the drug might mean that the desired rate and duration can not be obtained and that the beneficial effects of sustained release administration are lost.
  • a special challenge is met when trying to formulate water soluble substances for sustained release formulations.
  • One way to try to solve this problem would be to include large amounts of slow release exipients in the formulation.
  • this approach has drawbacks such as increased costs and increased size of the formulation.
  • Increased physical size of the dosage form may present problems for some patients, since the tablet will be more difficult to swallow.
  • Another possibility is to use a less water soluble salt.
  • such a change requires a more extensive development work and may also lead to bioavailability problems due to incomplete dissolution.
  • Hypercholesterolemia is related to an increased risk of coronary heart diseases.
  • a possible way to reduce cholesterol levels in a patient is to inhibit the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, which is a key enzyme in the regulation of cholesterol biosynthesis.
  • HMG-CoA reductase inhibitors constitute a well known group of therapeutic agents for the treatment of hypercholesterolemia, which group comprises fermentation products such as lovastatin and pravastatin, as well as semi-synthetic analogs such as simvastatin. More recently have completely synthetic drugs, e.g. fluvastatin, been developed.
  • HMG-CoA reductase inhibitors for the preparation of a medicament adapted for time-controlled administration is disclosed in EP-B-0 375 156.
  • Fluvastatin (R*,S*-(E)-( ⁇ )-7-[3-(4-fluorophenyl)-1-(1-methyl-ethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid) is known from EP-A-0 114 027.
  • Fluvastatin is a water soluble drug.
  • the solubility of the sodium salt of fluvastatin in water extends to more than 50 g/l. Biopharmaceutical requirements of a sustained release product of this water soluble drug would then at first sight impose formulation problems, as discussed above.
  • a diffusion controlled release device for this soluble substance e.g. an insoluble matrix of a polymer
  • fast release rates can be expected due to the high solubility of fluvastatin creating high concentration gradients as the driving force for diffusion out of the matrix.
  • an eroding matrix of fluvastatin is not expected to be useful due to the high concentrations of the drug in solution that can be the result when the gastrointestinal fluid penetrates the matrix.
  • the erosion of the matrix e.g. by dissolution of the outer hydrated polymer layers, would then indeed not be a rate controlling factor, except perhaps only for a first initial short time during hydration and swelling of the matrix.
  • FIG. 1 Release of fluvastatin and methylparaben, and tablet erosion, from sustained-release tablets based on polyethylene oxide (PEO) 8,000,000.
  • PEO polyethylene oxide
  • FIG. 2 Release of fluvastatin, methylparaben and diclofenac from sustained-release tablets based on xanthane.
  • FIG. 3 Release of fluvastatin and methylparaben from sustained-release tablets based on paraffin, and release of fluvastatin from immediate release (IR) capsules.
  • FIG. 4 Release rate of fluvastatin and diclofenac over a polymeric membrane in a two-compartment cell at different concentrations in donor chamber.
  • sustained-release compositions comprising fluvastatin as a water soluble salt, exhibit particularly favorable release characteristics such as unexpectedly long duration and slow rate of drug release.
  • water soluble should be understood as a solubility of more than 30 mg/ml in water at +37° C.
  • the present invention provides a pharmaceutical composition for sustained release comprising a water soluble salt, preferably the sodium salt, of fluvastatin as an active ingredient.
  • a sustained-release fluvastatin compositions for which these favorable properties are obtained are selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.
  • the said eroding and non-eroding matrix formulations can be based on hydrophilic and/or hydrophobic matrix forming excipients.
  • the matrix and membrane coated formulations may be monolithic, such as tablets, or in the form of multiple units administered in a tablet, capsule or sachets.
  • hydrophilic or hydrophobic, eroding or non-eroding, matrix material and the material for film formation can be, but is not limited to:
  • cellulose derivatives such as ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, cellulose acetate butyrate, cellulose acetate phtalate, etc;
  • polysaccharides like alginate; xanthane; carrageenan; scleroglucan; pullulan; dextran; haluronic acid; chitin; chitosan; starch; etc;
  • proteins e.g. albumin, gelatine
  • natural rubber etc;
  • synthetic polymers like acrylates (e.g. polymethacrylate, poly(hydroxy ethyl methacrylate), poly(methylmethacrylate), poly(hydroxy ethyl methacrylate-co methyl methacrylate), Carbopol 934TM); polyamindes (e.g. polyacrylamide, poly(methylene bisacrylamide)); polyanhydrides (e.g. poly(bis carboxyphenoxy)methane); PEO-PPO block-co-polymers (e.g.
  • polystyrene polyvinyl chloride; polyvinyl pyrrolidone; polyvinyl acetate; polyvinyl alcohol; polyethylene, polyethylene glycols and co-polymers thereof; polyethylene oxides and co-polymers thereof; polypropylene and co-polymers thereof; polystyrene; polyesters (e.g. poly(lactic acid), poly(glycolic acid), poly(caprolactone), etc, and co-polymers thereof, and poly(ortho esters), and co-polymers thereof); resins (e.g. DowexTM, AmberliteTM); polycarbonate; cellophane; silicones (e.g. poly(dimethylsiloxane)); polyurethanes; synthetic rubbers (e.g. styrene butadiene rubber, isopropene rubber); etc;
  • polyesters e.g. poly(lactic acid), poly(glycolic acid), poly(caprolactone), etc, and co-polymers
  • shellacs like shellacs; waxes (e.g. carnauba wax, beeswax, glycowax, castor wax); nylon; stearates (e.g. glycerol palnitostearate, glyceryl monostearate, glyceryl tristearate, stearyl alcohol); lipids (e.g. glycerides, phospholipids); paraffin; etc.
  • waxes e.g. carnauba wax, beeswax, glycowax, castor wax
  • nylon stearates (e.g. glycerol palnitostearate, glyceryl monostearate, glyceryl tristearate, stearyl alcohol); lipids (e.g. glycerides, phospholipids); paraffin; etc.
  • stearates e.g. glycerol palnitostearate, glyceryl monostearate, g
  • the invention provides a pharmaceutical composition as described above which is an eroding matrix formulation, wherein the matrix material is selected from the group comprising polyethylene oxide, hydroxypropyl methyl cellulose and paraffin.
  • the said pharmaceutical composition is a non-eroding matrix formulation, wherein the matrix material is selected from the group comprising xanthane and polyvinylchloride.
  • the said pharmaceutical composition is a diffusion-controlled membrane coated formulation, wherein the material for film formation is selected from the group comprising ethyl cellulose, hydroxypropyl methyl cellulose and hydoxypropyl cellulose.
  • fluvastatin comprises both of the pure enantiomers, as well as racemic mixtures.
  • the water soluble salts of fluvastatin to be used in the compositions according to the invention comprise e.g. the sodium, potassium, ammonium salts.
  • the sodium salt is preferred.
  • the pharmaceutical formulations according to the invention are useful for lowering the blood cholesterol level in animals, in particular mammals, e.g. humans. They are therefore useful as hypercholesterolemic and anti-atherosclerotic agents.
  • the invention provides in another aspect the use of fluvastatin for the manufacture of a pharmaceutical composition for sustained release, for the treatment of hypercholesterolemia.
  • the said composition is selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.
  • the invention provides a method for the treatment of hypercholesterolemia comprising administering to a mammal, including man, a therapeutically effective amount of a pharmaceutical composition for sustained release, comprising fluvastatin.
  • a pharmaceutical composition for sustained release comprising fluvastatin.
  • the said composition is selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.
  • the pharmaceutical formulations according to the invention can be prepared by use of well known pharmaceutical processing techniques such as blending, granulation, milling, spray drying, compaction, or coating.
  • sustained-release dosages will be in the range of 1 to 1000 mg of fluxvastatin per day, preferably 2 to 200 mg/day.
  • Methylparaben and diclofenac sodium could be expected to exhibit a somewhat slower release rate and longer duration of release, due to the lower water solubility.
  • the release of fluvastatin was consistently slower than methylparaben and diclofenac sodium for all the tested types of sustained-release formulations.
  • Fluvastatin or methylparaben (10 mg each) were formulated in an eroding matrix of PEO 8,000,000 (58 mg) and magnesium stearate (0.7 mg). Tablet erosion was determined by weighing after removal of the tablets from the dissolution apparatus and drying to constant weight.
  • Fluvastatin, methylparaben or diclofenac (5 mg each) were formulated in a non-eroding matrix of xanthane (195 mg).
  • Fluvastatin or diclofenac (20 mg each) were formulated in an eroding matrix of paraffin (120 mg), lactose (30 mg), ethyl cellulose (3 mg) and magnesium stearate (1.7 mg).
  • the immediate release capsule was a hard gelatine capsule containing 20 mg of fluvastatin.
  • the drug release for the immediate release capsule was almost immediate in contrast to the duration of drug release of more than 10 hours for fluvastatin sustained-release. This result indicates that the unexpectedly slow release for fluvastatin is not a general property for all kinds of oral fluvastatin formulations, but is limited to certain types of sustained release formulations according to the invention.
  • the release rate of fluvastatin sodium and diclofenac sodium was studied over a polymeric membrane from a donor compartment initially containing all drug substance, thus corresponding to a membrane coated formulation containing the active drug, to a receiving chamber which simulated the medium where the drug is released.
  • the release rate was studied at different initial concentrations of the active drug.
  • the solutions (pH 6.8) in the chambers were well stirred and thermostated at +37° C. From the cumulative amount released versus time, the release rates (amount released/time) were determined as the slopes of the linear parts of the curves obtained at steady state. No accumulation in the membrane was found of any of the drugs.
  • the results are presented in FIG. 4 as the release rates versus the concentrations used in the experiments.
  • the release rate of diclofenac increased as expected when the concentration of diclofenac was increased in the donor chamber.
  • the release rate of fluvastatin was independent of the concentration of fluvastatin in the donor compartment, resulting in a release rate of fluvastatin that was much slower compared to diclofenac. This strengthens that an unexpectedly slow release rate can be maintained for fluvastatin in such formulations irrespective of the amount of dissolved drug within a membrane coated formulations.
  • a dosage form adapted, designed and shaped for the oral delivery of fluvastatin sodium to a patient in need of fluvastatin therapy is manufactured as follows: first 30.0 g of fluvastatin sodium, 90.0 g of paraffin, 50.0 g calcium carbonate and 20.0 g sorbitol are screened through a 1.0 mm screen. The screened material are mixed in a planetary mixer for 10 minutes to produce a homogenous blend. Then, a granulation solution is prepared by dissolving 2.0 g ethyl cellulose (10 cps) in 150.0 g 95% ethanol during constant stirring for 6 hours. The granulation solution is slowly added to the dry mixture during agitation, to yield a wet granulation.
  • the granulation is dried at +50° C. for 12 hours. After drying, the granulation is passed through a screen of 1.5 mm. Magnesium stearate (2.0 g) is mixed in to the granulate for 3 minutes. Then, 8 mm round tablets, each comprising 30 mg of fluvastatin sodium are compressed in a Korsch® press under a pressure of 25 kN.
  • Fluvastatin sodium (20.0 g), 150.0 g of hydroxypropyl methyl cellulose (molecular weight 30,000), 30.0 g of sorbitol, 30.0 g of sodium aluminium silicate are dry mixed in a planetary mixer for 5 minutes. Then, a granulation solution is prepared by dissolving 10.0 g of polyvinyl pyrrolidone (molecular weight 360,000) in 200 g of 99.5% ethanol. The granulation solution is slowly added to the dry mixture during agitation, to yield a wetted mass. The granulation is dried overnight at +60° C. Next, the granulation is milled in a oscillating granulator through a screen of 0.7 mm.
  • Magnesium stearate (2.0 g) is mixed with the granulation for 2 minutes. Then, extended release round 10 mm tablets are prepared by compressing the composition with a 30 kN compression force. This fluvastatin tablet comprises 20 mg of fluvastatin sodium.
  • Fluvastatin tablets is manufactured as follows: first, 3 g of fluvastatin sodium, 20 g of 30,000 molecular weight hydroxypropyl methyl cellulose, 10 g of sodium aluminium silicate and 0.2 g carboxypolymethylene are dry mixed. Then, a granulation solution is prepared by dissolving 2.0 g ethyl cellulose (10 cps) in 20.0 g 99.5% ethanol. The granulation solution is slowly added to the dry mixture during agitation, to yield a wet granulation. The granulate is dried for 12 hours in 45° C. Next, the granulation is passed through a 1.0 mm screen. Sodium stearyl fumarate (0.8 g) is mixed with the granulation for 2 minutes. Then, extended release round 11 mm tablets are prepared by compressing with a 25 kN compression force. This fluvastatin tablet comprises 20 mg of fluvastatin sodium.
  • the beads obtained are coated with the polymeric layer controlling the release from the pellet, example of this coating is described below.
  • the polymeric mixture is dissolved in an organic solvent such as ethanol, isopropyl alcohol and/or methylene chloride.
  • the spraying can be carried out in a coating pan, but is preferably carried out in a fluidized bed.
  • Fluvastatin sodium 300 g Methylene chloride 2000 g Ethanol 99.5% 1000 g SiO 2 (0.15-0.25) 100 g
  • Polymeric layer Ethyl cellulose 10 cps 65.0 g Hydroxypropyl methyl cellulose 15.0 g Acetyltributyl citrate 9.0 g Methylene chloride 1500 g Isopropylic alcohol 350 g
  • a solution is prepared by dissolving fluvastatin sodium in 99.5%. ethanol and methylene chloride, the solution is then sprayed onto the cores of silicon dioxide in a fluidized bed.
  • 100 g of the beads (fraction 0.4-0.65 mm) are covered with the polymeric layer containing ethyl cellulose 10 cps, hydroxypropyl methyl cellulose and acetyltributyl citrate by spraying a solution of the mentioned substances in methylene chloride and isopropylic alcohol.
  • the coated beads are then filled into hard gelatin capsules.

Abstract

The present invention relates to pharmaceutical compositions for sustained release comprising a water soluble salt of the HMG-CoA reductase inhibitor fluvastatin as active ingredient, said composition being selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.

Description

    TECHNICAL FIELD
  • The present invention relates to pharmaceutical compositions for sustained release comprising a water soluble salt of the HMG-CoA reductase inhibitor fluvastatin as active ingredient, said composition being selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.
  • BACKGROUND ART
  • Sustained-release Compositions
  • In recent years there has been a large increase in the development and use of sustained-release tablets which are designed to release the drug slowly after ingestion. With these types of dosage forms, the clinical utility of drugs can be improved by means of improved therapeutic effects, reduced incidence of adverse effects and simplified dosing regimens.
  • A sustained-release tablet releases the drug during several hours, typically more than 3 hours and less than 30 hours. Other commonly used terms such as “controlled release”, “extended release”, “prolonged release”, etc., all comply with the definition of a product that releases the drug typically over more than 3 hours.
  • Several different types of formulations exist to obtain sustained release of a drug. The different formulations all aim to have release of the drug from the formulation, rather than the absorption process of the drug, as the rate limiting step. For this purpose, approaches based on the control of, e.g., dissolution, diffusion, swelling, osmotic pressure, complexation, ion-exchange, etc., can be employed. The actual approach taken for a given drug depends inter alia on the physical chemical properties of the drug. One of these is the solubility of the drug, which has a major impact on the pharmaceutical formulation strategy. A high solubility of the drug substance may induce problems, as discussed further below. However, in general, sustained release can be obtained according to the following principles, or combinations of them:
  • (i) By formulating the drug in an insoluble matrix. The gastrointestinal fluid penetrates the matrix, the drug is dissolved and diffuses out of the matrix and is absorbed. The driving force for diffusion is the concentration of the drug in the aqueous solution created by the penetrating gastrointestinal fluid. Thus, the higher the solubility, the higher the aqueous concentration of the drug in the matrix, and the faster the diffusional transport of the drug out of the matrix. If the matrix is a swelling matrix, e.g. a crosslinked (ionic) polymer with entrapped solid drug, the swelling kinetics of the matrix, the dissolution rate of the drug, and the diffusion of the drug will all contribute to the overall release rate. However, if the solubility of the drug is high, the release rate will be characterized by the diffusional transport after an initial swelling has occurred.
  • A similar principle applies when drug particles or cores containing the active drug are coated with an insoluble but porous membrane of polymers. In this case, the gastrointestinal fluids penetrates the membrane, the drug is dissolved and thereafter diffuses out of the coated particle through the membrane. The driving force for diffusion is the concentration of the drug in the aqueous solution created by the penetrating gastrointestinal fluid. Thus, the higher the solubility, the higher the aqueous concentration of the drug in the matrix, and the faster the diffusional transport of the drug over the membrane. It can be argued that the transport rate with this type of formulation is dictated by the pores in the membrane. Nevertheless, it is the solubility which creates a high concentration gradient over the membrane and which then is important for the transport rate from the formulation.
  • (ii) By formulating the drug in an eroding matrix of, e.g. a soluble polymer. The rate with which the drug will be available at the absorption site is for these matrices a combination of the swelling and erosion rates of the matrix, and the dissolution and diffusion rates of the drug. A formulation based on this principle for a soluble drug might not show acceptable sustained release due to the high concentration gradient of the drug that can be created after an initial swelling of the polymer, leading to a diffusional transport of the drug instead of a release controlled by the erosion, i.e. the dissolution of the polymer.
  • (iii) Release controlled by osmotic pressure, whereby a semipermeable membrane is placed around a tablet or drug particle which allows transport of water into the formulation by osmosis. As a result of increased internal pressure when the drug dissolves, drug solution is then pumped out of the tablet through a small hole in the coating. The size of the orifice in the coating controls both the volume flow into the core reservoir, and the drug solution release rate. If the drug has a high solubility, the size of the orifice must be made small to prolong the release rate. This might then create problems with the possible build up of a high hydraulic pressure inside the device until the walls ruptures.
  • Improved drug delivery by sustained release has been discussed more extensively in the literature, e.g. in:
  • Langer and Wise (Eds.) “Medical Applications of Controlled Release”, vols I and II, CRC Press Inc, Boca Raton, 1984;
  • Robinson and Lee (Eds.) “Controlled Drug Delivery—fundamentals and applications”, Marcel Dekker, NY, 1987;
  • Bogentoft and Sjogren, in “Towards Better Safety of Drugs and Pharmaceutical Products” (Ed: Breimer), Elsevier, 1980.
  • As mentioned above, the drug release from sustained release formulations is related to the drug solubility. The higher the water solubility of the drug, the faster the drug release and the shorter the duration of drug delivery. A fast release of the drug might mean that the desired rate and duration can not be obtained and that the beneficial effects of sustained release administration are lost. Thus, a special challenge is met when trying to formulate water soluble substances for sustained release formulations. One way to try to solve this problem would be to include large amounts of slow release exipients in the formulation. However, this approach has drawbacks such as increased costs and increased size of the formulation. Increased physical size of the dosage form may present problems for some patients, since the tablet will be more difficult to swallow. Another possibility is to use a less water soluble salt. However, such a change requires a more extensive development work and may also lead to bioavailability problems due to incomplete dissolution.
  • HMG-CoA Reductase Inhibitors
  • Hypercholesterolemia is related to an increased risk of coronary heart diseases. A possible way to reduce cholesterol levels in a patient is to inhibit the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, which is a key enzyme in the regulation of cholesterol biosynthesis. The HMG-CoA reductase inhibitors constitute a well known group of therapeutic agents for the treatment of hypercholesterolemia, which group comprises fermentation products such as lovastatin and pravastatin, as well as semi-synthetic analogs such as simvastatin. More recently have completely synthetic drugs, e.g. fluvastatin, been developed.
  • The use of some HMG-CoA reductase inhibitors for the preparation of a medicament adapted for time-controlled administration is disclosed in EP-B-0 375 156.
  • Fluvastatin (R*,S*-(E)-(±)-7-[3-(4-fluorophenyl)-1-(1-methyl-ethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid) is known from EP-A-0 114 027.
    Figure US20070031493A1-20070208-C00001
  • Fluvastatin is a water soluble drug. For example, the solubility of the sodium salt of fluvastatin in water extends to more than 50 g/l. Biopharmaceutical requirements of a sustained release product of this water soluble drug would then at first sight impose formulation problems, as discussed above. Thus, with a diffusion controlled release device for this soluble substance, e.g. an insoluble matrix of a polymer, fast release rates can be expected due to the high solubility of fluvastatin creating high concentration gradients as the driving force for diffusion out of the matrix.
  • Second, an eroding matrix of fluvastatin is not expected to be useful due to the high concentrations of the drug in solution that can be the result when the gastrointestinal fluid penetrates the matrix. The erosion of the matrix, e.g. by dissolution of the outer hydrated polymer layers, would then indeed not be a rate controlling factor, except perhaps only for a first initial short time during hydration and swelling of the matrix.
  • Finally, advanced techniques with high production costs are expected to be necessary to produce osmotic pressure controlled formulations. The high solubility of fluvastatin is also expected to complicate the action of such formulations. Thus, a small orifice would be needed in order to keep the rate low with which the amount of drug is pumped out through such devices. With a small orifice, however, the hydrostatic pressure that will be built up would put demands on the choice of a strong polymer membrane.
  • Consequently, there is a need for pharmaceutical formulations of HMG-CoA reductase inhibitors which avoid the above mentioned drawbacks and are possible to prepare, e.g., without including large amounts of slow release excipients or the use of highly advanced techniques. Preferably, the production costs of the formulations should be low.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1: Release of fluvastatin and methylparaben, and tablet erosion, from sustained-release tablets based on polyethylene oxide (PEO) 8,000,000.
  • FIG. 2:. Release of fluvastatin, methylparaben and diclofenac from sustained-release tablets based on xanthane.
  • FIG. 3: Release of fluvastatin and methylparaben from sustained-release tablets based on paraffin, and release of fluvastatin from immediate release (IR) capsules.
  • FIG. 4: Release rate of fluvastatin and diclofenac over a polymeric membrane in a two-compartment cell at different concentrations in donor chamber.
  • DISCLOSURE OF THE INVENTION
  • It has surprisingly been found that sustained-release compositions, comprising fluvastatin as a water soluble salt, exhibit particularly favorable release characteristics such as unexpectedly long duration and slow rate of drug release. In the present context, the term “water soluble” should be understood as a solubility of more than 30 mg/ml in water at +37° C.
  • Consequently, the present invention provides a pharmaceutical composition for sustained release comprising a water soluble salt, preferably the sodium salt, of fluvastatin as an active ingredient. The sustained-release fluvastatin compositions for which these favorable properties are obtained are selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.
  • The said eroding and non-eroding matrix formulations can be based on hydrophilic and/or hydrophobic matrix forming excipients. The matrix and membrane coated formulations may be monolithic, such as tablets, or in the form of multiple units administered in a tablet, capsule or sachets.
  • The hydrophilic or hydrophobic, eroding or non-eroding, matrix material and the material for film formation, can be, but is not limited to:
  • cellulose derivatives such as ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, cellulose acetate butyrate, cellulose acetate phtalate, etc;
  • polysaccharides, like alginate; xanthane; carrageenan; scleroglucan; pullulan; dextran; haluronic acid; chitin; chitosan; starch; etc;
  • other natural polymers, like proteins (e.g. albumin, gelatine); natural rubber; etc;
  • synthetic polymers, like acrylates (e.g. polymethacrylate, poly(hydroxy ethyl methacrylate), poly(methylmethacrylate), poly(hydroxy ethyl methacrylate-co methyl methacrylate), Carbopol 934™); polyamindes (e.g. polyacrylamide, poly(methylene bisacrylamide)); polyanhydrides (e.g. poly(bis carboxyphenoxy)methane); PEO-PPO block-co-polymers (e.g. poloxamers, etc); polyvinyl chloride; polyvinyl pyrrolidone; polyvinyl acetate; polyvinyl alcohol; polyethylene, polyethylene glycols and co-polymers thereof; polyethylene oxides and co-polymers thereof; polypropylene and co-polymers thereof; polystyrene; polyesters (e.g. poly(lactic acid), poly(glycolic acid), poly(caprolactone), etc, and co-polymers thereof, and poly(ortho esters), and co-polymers thereof); resins (e.g. Dowex™, Amberlite™); polycarbonate; cellophane; silicones (e.g. poly(dimethylsiloxane)); polyurethanes; synthetic rubbers (e.g. styrene butadiene rubber, isopropene rubber); etc;
  • others, like shellacs; waxes (e.g. carnauba wax, beeswax, glycowax, castor wax); nylon; stearates (e.g. glycerol palnitostearate, glyceryl monostearate, glyceryl tristearate, stearyl alcohol); lipids (e.g. glycerides, phospholipids); paraffin; etc.
  • Combinations of the above mentioned materials are also possible.
  • In a preferred form, the invention provides a pharmaceutical composition as described above which is an eroding matrix formulation, wherein the matrix material is selected from the group comprising polyethylene oxide, hydroxypropyl methyl cellulose and paraffin.
  • In another preferred form, the said pharmaceutical composition is a non-eroding matrix formulation, wherein the matrix material is selected from the group comprising xanthane and polyvinylchloride.
  • In yet another preferred form, the said pharmaceutical composition is a diffusion-controlled membrane coated formulation, wherein the material for film formation is selected from the group comprising ethyl cellulose, hydroxypropyl methyl cellulose and hydoxypropyl cellulose.
  • In the present context, the term “fluvastatin” comprises both of the pure enantiomers, as well as racemic mixtures.
  • The water soluble salts of fluvastatin to be used in the compositions according to the invention comprise e.g. the sodium, potassium, ammonium salts. The sodium salt is preferred.
  • The pharmaceutical formulations according to the invention are useful for lowering the blood cholesterol level in animals, in particular mammals, e.g. humans. They are therefore useful as hypercholesterolemic and anti-atherosclerotic agents.
  • Consequently, the invention provides in another aspect the use of fluvastatin for the manufacture of a pharmaceutical composition for sustained release, for the treatment of hypercholesterolemia. Preferably, the said composition is selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.
  • In yet another aspect, the invention provides a method for the treatment of hypercholesterolemia comprising administering to a mammal, including man, a therapeutically effective amount of a pharmaceutical composition for sustained release, comprising fluvastatin. Preferably, the said composition is selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.
  • The pharmaceutical formulations according to the invention can be prepared by use of well known pharmaceutical processing techniques such as blending, granulation, milling, spray drying, compaction, or coating.
  • The typical daily dose of the active substance fluvastatin varies within a wide range and will depend on various factors such as for example the individual requirement of each patient and the disease. In general, sustained-release dosages will be in the range of 1 to 1000 mg of fluxvastatin per day, preferably 2 to 200 mg/day.
  • EXAMPLES OF THE INVENTION
  • To exemplify the unexpectedly favorable properties of fluvastatin in matrix formulations and membrane coated formulations, the release profile of fluvastatin sodium (water solubility>50 mg/ml) was compared with two other water soluble drugs, namely methylparaben (methyl p-hydroxybenzoate; water solubility≈2 mg/ml) and diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid monosodium salt; water solubility≈5 mg/ml).
    Figure US20070031493A1-20070208-C00002
  • Methylparaben and diclofenac sodium could be expected to exhibit a somewhat slower release rate and longer duration of release, due to the lower water solubility. However, unexpectedly, the release of fluvastatin was consistently slower than methylparaben and diclofenac sodium for all the tested types of sustained-release formulations.
  • In the following Examples 1 to 3, drug release from various types of tablets was determined in pH 6.8, +37° C., by use of an USP II apparatus at a paddle stirring rate of 75 rpm. All tablet formulations were manufactured by conventional techniques and, for each example, in an identical manner except for the drug constituent.
  • Example 1 Drug Release and Tablet Erosion for Eroding Polyethyleneoxide (PEO) Matrix Tablet
  • Fluvastatin or methylparaben (10 mg each) were formulated in an eroding matrix of PEO 8,000,000 (58 mg) and magnesium stearate (0.7 mg). Tablet erosion was determined by weighing after removal of the tablets from the dissolution apparatus and drying to constant weight.
  • The results (FIG. 1) show that release of fluvastatin from the sustained release tablet was slower than the release of methylparaben in spite of the higher solubility. The tablet erosion and drug release was almost identical for fluvastatin whereas for the methylparaben tablet, as could be expected for a water soluble drug, the drug release was faster than the tablet erosion. This was a further indication that fluvastatin has unexpectedly favourable extended release properties when administered as an eroding matrix tablet both compared to what could expected from tablet erosion data and compared to another somewhat less soluble drug.
  • Example 2 Release from a Non Eroding High Molecular Weight Xanthane Matrix Tablet
  • Fluvastatin, methylparaben or diclofenac (5 mg each) were formulated in a non-eroding matrix of xanthane (195 mg).
  • The results (FIG. 2) show that release of fluvastatin from the sustained release tablet was slower than the release of both diclofenac and methylparaben despite the higher solubility. This provides an example that fluvastatin has unexpectedly favourable extended release properties when administered as a non-eroding matrix tablet.
  • Example 3 Release from Eroding Paraffin Matrix Tablet and From a Conventional (Immediate Release) Hard Gelatin Capsule
  • Fluvastatin or diclofenac (20 mg each) were formulated in an eroding matrix of paraffin (120 mg), lactose (30 mg), ethyl cellulose (3 mg) and magnesium stearate (1.7 mg). The immediate release capsule was a hard gelatine capsule containing 20 mg of fluvastatin.
  • The results (FIG. 3) show that release of fluvastatin from the sustained release tablet was slower than the release of diclofenac despite the higher solubility. This provides another example that fluvastatin has unexpectedly favorable extended release properties when administered as a matrix tablet.
  • The drug release for the immediate release capsule was almost immediate in contrast to the duration of drug release of more than 10 hours for fluvastatin sustained-release. This result indicates that the unexpectedly slow release for fluvastatin is not a general property for all kinds of oral fluvastatin formulations, but is limited to certain types of sustained release formulations according to the invention.
  • Example 4 Transport Over a Diffusion Controlling Membrane
  • The release rate of fluvastatin sodium and diclofenac sodium was studied over a polymeric membrane from a donor compartment initially containing all drug substance, thus corresponding to a membrane coated formulation containing the active drug, to a receiving chamber which simulated the medium where the drug is released. The release rate was studied at different initial concentrations of the active drug. The solutions (pH 6.8) in the chambers were well stirred and thermostated at +37° C. From the cumulative amount released versus time, the release rates (amount released/time) were determined as the slopes of the linear parts of the curves obtained at steady state. No accumulation in the membrane was found of any of the drugs. The results are presented in FIG. 4 as the release rates versus the concentrations used in the experiments.
  • The release rate of diclofenac increased as expected when the concentration of diclofenac was increased in the donor chamber. However, surprisingly the release rate of fluvastatin was independent of the concentration of fluvastatin in the donor compartment, resulting in a release rate of fluvastatin that was much slower compared to diclofenac. This strengthens that an unexpectedly slow release rate can be maintained for fluvastatin in such formulations irrespective of the amount of dissolved drug within a membrane coated formulations.
  • Example 5 Manufacture of Pharmaceutical Formulations
  • 5.1.
  • A dosage form adapted, designed and shaped for the oral delivery of fluvastatin sodium to a patient in need of fluvastatin therapy is manufactured as follows: first 30.0 g of fluvastatin sodium, 90.0 g of paraffin, 50.0 g calcium carbonate and 20.0 g sorbitol are screened through a 1.0 mm screen. The screened material are mixed in a planetary mixer for 10 minutes to produce a homogenous blend. Then, a granulation solution is prepared by dissolving 2.0 g ethyl cellulose (10 cps) in 150.0 g 95% ethanol during constant stirring for 6 hours. The granulation solution is slowly added to the dry mixture during agitation, to yield a wet granulation. The granulation is dried at +50° C. for 12 hours. After drying, the granulation is passed through a screen of 1.5 mm. Magnesium stearate (2.0 g) is mixed in to the granulate for 3 minutes. Then, 8 mm round tablets, each comprising 30 mg of fluvastatin sodium are compressed in a Korsch® press under a pressure of 25 kN.
  • 5.2.
  • Fluvastatin sodium (20.0 g), 150.0 g of hydroxypropyl methyl cellulose (molecular weight 30,000), 30.0 g of sorbitol, 30.0 g of sodium aluminium silicate are dry mixed in a planetary mixer for 5 minutes. Then, a granulation solution is prepared by dissolving 10.0 g of polyvinyl pyrrolidone (molecular weight 360,000) in 200 g of 99.5% ethanol. The granulation solution is slowly added to the dry mixture during agitation, to yield a wetted mass. The granulation is dried overnight at +60° C. Next, the granulation is milled in a oscillating granulator through a screen of 0.7 mm. Magnesium stearate (2.0 g) is mixed with the granulation for 2 minutes. Then, extended release round 10 mm tablets are prepared by compressing the composition with a 30 kN compression force. This fluvastatin tablet comprises 20 mg of fluvastatin sodium.
  • 5.3.
  • Fluvastatin sodium (10 g), 50 g of 8,000,000 molecular weight polyethylene oxide, 50 g lactose are dry mixed. Then, 60 g of 99.5% ethanol and the dry mixture are slowly mixed together in a planetary mixer for 5 minutes. The granulate is dried for 12 hours in +45° C. Next, the granulation is passed through a 1.0 mm screen. 1.0 g of magnesium stearate is mixed with the granulation for 2 minutes. Then, extended release round 8 mm tablets are prepared by compressing with a 20 kN compression force. This fluvastatin tablet comprises 10 mg of fluvastatin sodium.
  • 5.4.
  • Fluvastatin tablets is manufactured as follows: first, 3 g of fluvastatin sodium, 20 g of 30,000 molecular weight hydroxypropyl methyl cellulose, 10 g of sodium aluminium silicate and 0.2 g carboxypolymethylene are dry mixed. Then, a granulation solution is prepared by dissolving 2.0 g ethyl cellulose (10 cps) in 20.0 g 99.5% ethanol. The granulation solution is slowly added to the dry mixture during agitation, to yield a wet granulation. The granulate is dried for 12 hours in 45° C. Next, the granulation is passed through a 1.0 mm screen. Sodium stearyl fumarate (0.8 g) is mixed with the granulation for 2 minutes. Then, extended release round 11 mm tablets are prepared by compressing with a 25 kN compression force. This fluvastatin tablet comprises 20 mg of fluvastatin sodium.
  • 5.5.
  • After the initial forming of beads containing fluvastatin sodium, the beads obtained are coated with the polymeric layer controlling the release from the pellet, example of this coating is described below. The polymeric mixture is dissolved in an organic solvent such as ethanol, isopropyl alcohol and/or methylene chloride. The spraying can be carried out in a coating pan, but is preferably carried out in a fluidized bed.
    Fluvastatin sodium 300 g
    Methylene chloride 2000 g
    Ethanol 99.5% 1000 g
    SiO2 (0.15-0.25) 100 g
  • Polymeric layer
    Ethyl cellulose
    10 cps 65.0 g
    Hydroxypropyl methyl cellulose 15.0 g
    Acetyltributyl citrate 9.0 g
    Methylene chloride 1500 g
    Isopropylic alcohol 350 g
  • A solution is prepared by dissolving fluvastatin sodium in 99.5%. ethanol and methylene chloride, the solution is then sprayed onto the cores of silicon dioxide in a fluidized bed. 100 g of the beads (fraction 0.4-0.65 mm) are covered with the polymeric layer containing ethyl cellulose 10 cps, hydroxypropyl methyl cellulose and acetyltributyl citrate by spraying a solution of the mentioned substances in methylene chloride and isopropylic alcohol. The coated beads are then filled into hard gelatin capsules.

Claims (15)

1-13. (canceled)
14. A pharmaceutical composition having sustained release of fluvastatin following ingestion, said composition comprising a water-soluble salt of fluvastatin as active ingredient and a polymeric matrix formulation comprising at least one polymeric matrix material.
15. The pharmaceutical composition according to claim 14 wherein the water-soluble salt of fluvastatin is the sodium salt.
16. The pharmaceutical composition according to claim 14, wherein the matrix formulation is an eroding matrix formulation.
17. The pharmaceutical composition according to claim 14, wherein the at least one polymeric matrix material comprises polyethylene oxide, hydroxypropyl methyl cellulose, paraffin or a combination thereof.
18. The pharmaceutical composition according to claim 14, wherein the matrix formulation is a noneroding matrix formulation.
19. The pharmaceutical composition according to claim 18, wherein the at least one matrix material comprises xanthan, polyvinyl chloride or a combination thereof.
20. A pharmaceutical composition according to claim 14, which is a diffusion-controlled membrane coated formulation.
21. A pharmaceutical composition according to claim 20 wherein the material for matrix formation is selected from the group comprising ethyl cellulose, hydroxypropyl methyl cellulose and hydroxypropyl cellulose.
22. A method for the treatment of hypercholesterolemia comprising administering to a mammal a therapeutically effective amount of a pharmaceutical composition having sustained release of fluvastatin following ingestion, the composition comprising a water-soluble salt of fluvastatin as active ingredient and a polymeric matrix formulation comprising at least one polymeric matrix material.
23. The method according to claim 25 wherein the pharmaceutical composition is selected from the group comprising matrix formulations, diffusion-controlled membrane coated formulations; and combinations thereof.
24. The method according to claim 22, wherein the mammal is a human.
25. The pharmaceutical composition according to claim 16, wherein the at least one polymeric matrix material is a single matrix material selected from the group consisting of polyethylene oxide, hydroxypropyl methyl cellulose and paraffin.
26. The pharmaceutical composition according to claim 14, wherein the at least one polymeric matrix material comprises a cellulose derivative polymer matrix material.
27. The pharmaceutical composition according to claim 14, wherein the at least one polymeric matrix material comprises a synthetic polymer matrix material is selected from the group consisting of an acrylate, a polyamide, a polyanhydride, a PEO-PPO block-co-polymer, polyvinyl chloride, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl alcohol, a polyethylene, a polyethylene glycol, a co-polymer of a polyethylene glycol, polyethylene oxide, a co-polymer of polyethylene oxide, a polypropylene, a co-polymer of a polypropylene, a polystyrene, a polyester, a co-polymer of a polyester, a resin, a polycarbonate, cellophane, a silicone, a polyurethane, and a synthetic rubber.
US11/545,650 1996-10-08 2006-10-10 Pharmaceutical compositions Abandoned US20070031493A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/545,650 US20070031493A1 (en) 1996-10-08 2006-10-10 Pharmaceutical compositions
US12/795,801 US20100291217A1 (en) 1996-10-08 2010-06-08 Pharmaceutical compositions

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
SE9603667-8 1996-10-08
SE9603667A SE9603667D0 (en) 1996-10-08 1996-10-08 Pharmaceutical compositions
US08/945,655 US20030194440A1 (en) 1996-10-08 1997-09-24 Pharmaceutical composition for sustained release of the hmg-coa reductase inhibitor fluvastatin
PCT/SE1997/001604 WO1998015264A1 (en) 1996-10-08 1997-09-24 PHARMACEUTICAL COMPOSITIONS FOR SUSTAINED RELEASE OF THE HMG-CoA REDUCTASE INHIBITOR FLUVASTATIN
US10/738,196 US20040132814A1 (en) 1996-10-08 2003-12-17 Pharmaceutical compositions
US11/545,650 US20070031493A1 (en) 1996-10-08 2006-10-10 Pharmaceutical compositions

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/738,196 Division US20040132814A1 (en) 1996-10-08 2003-12-17 Pharmaceutical compositions

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/795,801 Continuation US20100291217A1 (en) 1996-10-08 2010-06-08 Pharmaceutical compositions

Publications (1)

Publication Number Publication Date
US20070031493A1 true US20070031493A1 (en) 2007-02-08

Family

ID=20404165

Family Applications (5)

Application Number Title Priority Date Filing Date
US08/945,655 Abandoned US20030194440A1 (en) 1996-10-08 1997-09-24 Pharmaceutical composition for sustained release of the hmg-coa reductase inhibitor fluvastatin
US10/738,196 Abandoned US20040132814A1 (en) 1996-10-08 2003-12-17 Pharmaceutical compositions
US11/545,650 Abandoned US20070031493A1 (en) 1996-10-08 2006-10-10 Pharmaceutical compositions
US12/795,774 Abandoned US20100291216A1 (en) 1996-10-08 2010-06-08 Pharmaceutical compositions
US12/795,801 Abandoned US20100291217A1 (en) 1996-10-08 2010-06-08 Pharmaceutical compositions

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US08/945,655 Abandoned US20030194440A1 (en) 1996-10-08 1997-09-24 Pharmaceutical composition for sustained release of the hmg-coa reductase inhibitor fluvastatin
US10/738,196 Abandoned US20040132814A1 (en) 1996-10-08 2003-12-17 Pharmaceutical compositions

Family Applications After (2)

Application Number Title Priority Date Filing Date
US12/795,774 Abandoned US20100291216A1 (en) 1996-10-08 2010-06-08 Pharmaceutical compositions
US12/795,801 Abandoned US20100291217A1 (en) 1996-10-08 2010-06-08 Pharmaceutical compositions

Country Status (13)

Country Link
US (5) US20030194440A1 (en)
EP (1) EP0948320B1 (en)
JP (2) JP4627810B2 (en)
AT (1) ATE236619T1 (en)
AU (1) AU4578097A (en)
CY (1) CY2469B1 (en)
DE (1) DE69720778T2 (en)
DK (1) DK0948320T3 (en)
ES (1) ES2197369T3 (en)
PT (1) PT948320E (en)
SE (1) SE9603667D0 (en)
SI (1) SI0948320T1 (en)
WO (1) WO1998015264A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9393224B2 (en) 2011-08-26 2016-07-19 Osaka University Prophylactic and/or therapeutic agent for cardiovascular complications of diabetes

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU5758799A (en) * 1998-09-25 2000-04-17 Sankyo Company Limited Hmg-coa reductase inhibitor-containing preparations
CO5140079A1 (en) * 1998-10-14 2002-03-22 Novartis Ag PHARMACEUTICAL COMPOSITION OF SUSTAINED LIBERATION AND METHOD TO RELEASE A PHARMACEUTICALLY ACTIVE AGENT FROM SUSTAINED LIBERATION AND METHOD TO RELEASE A PHARMACEUTICALLY ACTIVE AGENT
US6465011B2 (en) * 1999-05-29 2002-10-15 Abbott Laboratories Formulations comprising lipid-regulating agents
US6372251B2 (en) 1999-06-11 2002-04-16 Abbott Laboratories Formulations comprising lipid-regulating agents
ES2168043B1 (en) * 1999-09-13 2003-04-01 Esteve Labor Dr PHARMACEUTICAL FORM ORAL SOLID MODIFIED RELEASE CONTAINING A COMPOSITE OF BENCIMIDAZOL LABIL IN THE MIDDLE ACID.
DE19954421A1 (en) * 1999-11-12 2001-05-31 Lohmann Therapie Syst Lts Film-like preparation for the biphase release of pharmacologically active or other substances
US6242003B1 (en) 2000-04-13 2001-06-05 Novartis Ag Organic compounds
US20060127474A1 (en) 2001-04-11 2006-06-15 Oskar Kalb Pharmaceutical compositions comprising fluvastatin
GB0217306D0 (en) * 2002-07-25 2002-09-04 Novartis Ag Compositions comprising organic compounds
SI21400A (en) * 2003-02-12 2004-08-31 LEK farmacevtska družba d.d. Stable pharmaceutical form with hmg-coa reductase inhibitor
EA011746B1 (en) * 2004-05-24 2009-06-30 Никомед Фарма Ас Agglomeration of the calcium-containing compound by means of roller compaction
US20090124702A1 (en) * 2005-01-25 2009-05-14 Pechetti Siva Satya Krishna Babu Pharmaceutical Compositions of Metformin
US20060229277A1 (en) * 2005-04-08 2006-10-12 Orbus Pharma, Inc. Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor
EP1818050A1 (en) * 2006-02-10 2007-08-15 Stada Arzneimittel Ag Stable pharmaceutical compositions comprising a HMG-CoA reductase inhibitor
EP1825848A3 (en) * 2006-02-10 2010-03-03 Stada Arzneimittel Ag Stable pharmaceutical compositions comprising an HMG-CoA reductase inhibitor
EP1825847A3 (en) * 2006-02-24 2008-01-23 Teva Pharmaceutical Industries Ltd Fluvastatin sodium pharmaceutical compositions
AU2006343499A1 (en) * 2006-05-12 2007-11-22 Pharmathen S.A. Pharmaceutical formulation containing an HMG-CoA reductase inhibitor and method for the preparation thereof
EP1911441A3 (en) * 2006-10-11 2008-08-06 Lupin Limited Controlled release color stable pharmaceutical dosage form of HMG-COA reductase inhibitors, free of alkalizing or buffering agents
US20080132560A1 (en) * 2006-11-21 2008-06-05 San-Laung Chow Solid dispersion composition
IS8612A (en) * 2007-02-19 2008-08-20 Actavis Group Ptc Ehf. Stable statin formulations
WO2011094618A1 (en) * 2010-02-01 2011-08-04 Conocophillips Company Water-forming hydrogenation reactions utilizing enhanced catalyst supports and methods of use
US20130143867A1 (en) 2011-12-02 2013-06-06 Sychroneuron Inc. Acamprosate formulations, methods of using the same, and combinations comprising the same
CN102755284B (en) * 2011-12-22 2014-11-05 深圳信立泰药业股份有限公司 Fluvastatin sustained-release medicinal composition
WO2014197744A1 (en) 2013-06-05 2014-12-11 Synchroneuron, Inc. Acamprosate formulations, methods of using the same, and combinations comprising the same

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4915954A (en) * 1987-09-03 1990-04-10 Alza Corporation Dosage form for delivering a drug at two different rates
US5023089A (en) * 1988-07-18 1991-06-11 Shionogi & Co., Ltd. Sustained-release preparations and the process thereof
US5238686A (en) * 1986-03-27 1993-08-24 Kinaform Technology, Inc. Sustained-release pharmaceutical preparation
US5273758A (en) * 1991-03-18 1993-12-28 Sandoz Ltd. Directly compressible polyethylene oxide vehicle for preparing therapeutic dosage forms
US5316765A (en) * 1989-09-07 1994-05-31 Karl Folkers Foundation For Biomedical And Clinical Research Use of coenzyme Q10 in combination with HMG-CoA reductase inhibitor therapies
US5356896A (en) * 1991-12-12 1994-10-18 Sandoz Ltd. Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound
US5395696A (en) * 1992-04-10 1995-03-07 Fuji Photo Film Co., Ltd. Magnetic recording medium having a lubricant layer of a fluoroalkyl sulfo-compound
US5462749A (en) * 1991-09-25 1995-10-31 Mcnell-Ppc, Inc. Bioadhesive pharmaceutical carrier
US5576016A (en) * 1993-05-18 1996-11-19 Pharmos Corporation Solid fat nanoemulsions as drug delivery vehicles
US5674893A (en) * 1994-01-18 1997-10-07 Bristol-Myers Squibb Company Method for preventing reducing or risk of onset of cerebrovascular events employing an HMG CoA reductase inhibitor
US6020000A (en) * 1995-02-24 2000-02-01 Alza Corporatiton Banded prolonged release active agent dosage form

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3965255A (en) * 1974-05-01 1976-06-22 E. E. Eljim Ecology Ltd. Controlled drug releasing preparations
US4739073A (en) * 1983-11-04 1988-04-19 Sandoz Pharmaceuticals Corp. Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof
US5354772A (en) * 1982-11-22 1994-10-11 Sandoz Pharm. Corp. Indole analogs of mevalonolactone and derivatives thereof
GB8521494D0 (en) * 1985-08-29 1985-10-02 Zyma Sa Controlled release tablet
US4713243A (en) * 1986-06-16 1987-12-15 Johnson & Johnson Products, Inc. Bioadhesive extruded film for intra-oral drug delivery and process
US4997658A (en) * 1988-11-21 1991-03-05 Merck & Co., Inc. Method for enhancing the lowering of plasma cholesterol levels
CA2045428A1 (en) * 1990-06-26 1991-12-27 Alfred W. Alberts Method for enhancing the lowering of plasma cholesterol levels
US5130333A (en) * 1990-10-19 1992-07-14 E. R. Squibb & Sons, Inc. Method for treating type II diabetes employing a cholesterol lowering drug
US5395626A (en) * 1994-03-23 1995-03-07 Ortho Pharmaceutical Corporation Multilayered controlled release pharmaceutical dosage form
JP2849047B2 (en) * 1994-12-19 1999-01-20 大正薬品工業株式会社 Diclofenac sodium sustained-release preparation and its production method
US5837379A (en) * 1997-01-31 1998-11-17 Andrx Pharmaceuticals, Inc. Once daily pharmaceutical tablet having a unitary core

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5238686A (en) * 1986-03-27 1993-08-24 Kinaform Technology, Inc. Sustained-release pharmaceutical preparation
US4915954A (en) * 1987-09-03 1990-04-10 Alza Corporation Dosage form for delivering a drug at two different rates
US5023089A (en) * 1988-07-18 1991-06-11 Shionogi & Co., Ltd. Sustained-release preparations and the process thereof
US5316765A (en) * 1989-09-07 1994-05-31 Karl Folkers Foundation For Biomedical And Clinical Research Use of coenzyme Q10 in combination with HMG-CoA reductase inhibitor therapies
US5273758A (en) * 1991-03-18 1993-12-28 Sandoz Ltd. Directly compressible polyethylene oxide vehicle for preparing therapeutic dosage forms
US5462749A (en) * 1991-09-25 1995-10-31 Mcnell-Ppc, Inc. Bioadhesive pharmaceutical carrier
US5356896A (en) * 1991-12-12 1994-10-18 Sandoz Ltd. Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound
US5395696A (en) * 1992-04-10 1995-03-07 Fuji Photo Film Co., Ltd. Magnetic recording medium having a lubricant layer of a fluoroalkyl sulfo-compound
US5576016A (en) * 1993-05-18 1996-11-19 Pharmos Corporation Solid fat nanoemulsions as drug delivery vehicles
US5674893A (en) * 1994-01-18 1997-10-07 Bristol-Myers Squibb Company Method for preventing reducing or risk of onset of cerebrovascular events employing an HMG CoA reductase inhibitor
US6020000A (en) * 1995-02-24 2000-02-01 Alza Corporatiton Banded prolonged release active agent dosage form

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9393224B2 (en) 2011-08-26 2016-07-19 Osaka University Prophylactic and/or therapeutic agent for cardiovascular complications of diabetes

Also Published As

Publication number Publication date
SI0948320T1 (en) 2003-10-31
JP2009102339A (en) 2009-05-14
US20030194440A1 (en) 2003-10-16
DK0948320T3 (en) 2003-08-04
PT948320E (en) 2003-08-29
JP4627810B2 (en) 2011-02-09
WO1998015264A1 (en) 1998-04-16
AU4578097A (en) 1998-05-05
CY2469B1 (en) 2005-06-03
EP0948320A1 (en) 1999-10-13
US20040132814A1 (en) 2004-07-08
EP0948320B1 (en) 2003-04-09
DE69720778D1 (en) 2003-05-15
US20100291216A1 (en) 2010-11-18
US20100291217A1 (en) 2010-11-18
SE9603667D0 (en) 1996-10-08
DE69720778T2 (en) 2004-02-05
ES2197369T3 (en) 2004-01-01
ATE236619T1 (en) 2003-04-15
JP2001502671A (en) 2001-02-27

Similar Documents

Publication Publication Date Title
US20070031493A1 (en) Pharmaceutical compositions
RU2385712C2 (en) Controlled-release formulation
RU2179017C2 (en) Pharmaceutical composition for sustained-release of active substances (variants) and method of its preparing (variants)
AU2004268663B2 (en) Sustained release dosage forms of ziprasidone
KR101555455B1 (en) Osmotic drug delivery system comprising release enhancing agent
US7915247B1 (en) Methods of use of fenofibric acid
KR20110097829A (en) Solid composition for controlled release of ionizable active agents with poor aqueous solubility at low ph and methods of use thereof
CZ2003199A3 (en) Quick expanding composition for controlled release of a medicament and retention thereof in stomach and medicinal forms containing such composition
EP4249055A2 (en) Tofacitinib oral sustained release dosage forms
JP2001509157A (en) Time-specific controlled-release dosage formulation and its preparation
JP2003503341A (en) Pharmaceutical dosage forms for controlled release producing at least one timely pulse
MXPA04005667A (en) Extended release pharmaceutical tablet of metformin.
AU2002331094B2 (en) Pharmaceutical composition comprising lumiracoxib
WO2007141743A2 (en) A tablet dosage form comprising cetirizine and pseudoephedrine
EP2632428B1 (en) Modified starch derivative-based matrix for colon targeting
US8535716B2 (en) Methods and composition of extended delivery of water insoluble drugs
EP2277511B1 (en) Extended release pharmaceutical compositions of levetiracetam
EP4069207A1 (en) Modified release pharmaceutical compositions of riociguat
WO2007010508A2 (en) Controlled release compositions of metaxalone
Jethara et al. Aperito Journal of Drug Designing And Pharmacology
US8962020B2 (en) Long-acting and controlled release formulations of 2-[(3-chlorophenyl) amino] phenylacetic acid
JP2003146882A (en) Method for controlling elution speed of physiologically active substance-containing solid material

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION